Introduction

The order Xylariales comprises nearly 800 species in eight families, the most important of which is the Xylariaceae; it includes the genus Xylaria with over 100 species. Xylaria species are commonly found as saprophytes and endophytes (Webster and Weber 2007).

Fungal endophytes are found inside the living tissues of all plants and grow without causing apparent damage or disease in the host plant. These fungi are symbionts that can protect their host by producing enzymes or secondary metabolites that directly inhibit the action of microbial pathogens, plants growing around and animals; they can also protect them by inducing the host to synthesize secondary metabolites, or enzymes, that improve their defenses against pathogens and hervibores; moreover, they can occupy a niche in the plant tissues and hamper the colonization and infection by harmful microorganisms (Gao et al. 2010; Guzmán-Trampe et al. 2015).

Xylaria species are dominant, fast growing and generalist endophytes found in tropical plants (Arnold and Lutzoni 2007; Hyde and Soytong 2008). They have been isolated from vascular plants (conifers, monocots, dicots, ferns, and lycopsids) and from nonvascular plants (liverworts); (Davis et al. 2003). They produce secondary metabolites which are chemically diverse and biologically active (Song et al. 2014).

Endophytic fungi synthesize various bioactive secondary metabolites that may directly or indirectly be used as therapeutic agents or as biopesticides (Kusari et al. 2012; Guzmán-Trampe et al. 2015). The chemical diversity of secondary metabolites produced by Xylaria species includes terpenoids, suchs as eudesmanes and guaianes; cytochalasins, mellein, alkaloids, polyketides, and aromatic compounds; and volatile organic compounds (VOCs), including sesquiterpenoids, esters, and alcohols, among others (Song et al. 2014; Sánchez-Ortiz et al. 2016). The production of these bioactive secondary metabolites is characteristic of many mutualistic endophytes and favors the symbiosis in the host plant (Davis et al. 2003).

A comprehensive review about Xylaria was published in Song et al. (2014), it encompasses the secondary metabolites produced by species isolated not only as endophytes but also from different substrates, and their biological activities reported until 2012. In this review, we update this information by summing up recently reported secondary metabolites from endophytic species, with potential use in medicine and agriculture, according to their biological activity.

Medicinal potential

Antimicrobial agents

Five antimicrobial compounds were isolated from Xylaria sp. SNB-GTC2501, an endophyte of Bisboecklera microcephala gathered in French Guiana. The compounds include two new isopimarane diterpenoids, xylabisboein A (1) and B (2), and the three known compounds (−)-5-methylmellein (3), mellein-5-carboxylic acid or 5-carboxylmellein (4) and ergosterol peroxide (5). The minimal inhibitory concentration (MIC) values against Staphylococcus aureus, Trichophyton rubrum and Candida albicans were higher than 128 µg/mL for all the compounds (Sorres et al. 2015). Moreover, Chinworrungsee et al. (2001) demonstrated that 5-carboxylmellein (4) presents antimalarial activity against a multidrug resistant strain of Plasmodium falciparum K1 with an IC50 value of 4 µg/mL.

Xylaria sp. Acra L38, an endophyte isolated from Aquilaria crassna, a plant that grows in Thailand, produces zofimarin (6) (Chaichanan et al. 2014). Compound 6 is a selective antifungal with activity against C. albicans, including azole-resistant strains, Saccharomyces cerevisiae, Cryptococcus neoformans, and Aspergillus sp. It is important to note that zofimarin (6) was previously identified from a marine fungus, Zopfielle marina SANK21274, in 1987 and patented (Ogita et al. 1987; Vicente et al. 2003; Chaichanan et al. 2014). In addition, Chaichanan et al. (2014) optimized the fermentation medium for the production of the compound 6 and found that it was only produced when Czapek yeast extract culture medium was used and that sucrose, maltose, glucose and NaNO3 were important components for its production.

Xylaria sp., isolated from the orchid Anoectochilus setaceus from Sri Lanka, produces the antimicrobial helvolic acid (7). The nortriterpenoid 7 showed antibacterial activity against the Gram-positive bacteria Bacillus subtilis and methicillin-resistant S. aureus (MRSA) with MIC values of 2 and 4 μg/mL, respectively (Ratnaweera et al. 2014).

The compound 4-cyanomethoxy benzoic acid (8) was isolated from Xylaria sp. strain FPLX-10, an endophyte of Ficus pumila Linn. collected in India, by using a dereplication strategy (Rakshith et al. 2013). This compound was also identified from the Indonesian marine endophytic fungus Xylaria psidii KT30, isolated from the red alga Kappaphycus alvarezii (Tarman et al. 2011). Compound 8 showed antibacterial activity against Escherichia coli, Vibrio parahaemolyticus, S. aureus and Listeria monocytogenes and antifungal activity on C. albicans and Aspergillus niger in TLC–bioautographic assay (Rakshith et al. 2013).

The endophyte Xylaria sp. PSU-G12, isolated from a branch of Garcinia hombroniana gathered in Thailand, produces two new compounds: the mellein derivative xylarellein (9), and the indanone derivative xylariaindanone (10). Furthermore, seven known compounds were also isolated: (3R)-5-methylmellein (3), (3R)-5-carboxylmellein (4), 3-hydroxy-4-methyl-1-indanone (11), (3R)-5-carbomethoxymellein (12), cytochalasin D (13), griseofulvin (95), and dechlorogriseofulvin (96). The broth extract presented antioxidant activity on the DPPH assay, thus, compounds 3, 4, 12, 13, 95, and 96 were tested for antioxidant activity, however none of them were active (Rukachaisirikul et al. 2013). On the other hand, Pongcharoen et al. (2007) isolated the fungus Xylaria sp. BCC 9653 from an unidentified tree from Thailand, it yields 5-carboxylmellein (4) and cytochalasin D (13). Compounds 4 and 13 possess antimycobacterial activity against Mycobacterium tuberculosis, the MIC values were 394.3 and 900.7 µM, respectively.

Xylaria sp. NC1214, an endophyte isolated from Hypnum sp. collected in the United States (North Carolina), produces 1β,4β,7α-trihydroxyeudesmane (14) among other compounds (Wei et al. 2015). The eudesmane terpene 14 inhibited the growth of Shigella sonnei, M. tuberculosis and an α-hemolytic Streptococcus with a minimal inhibitory amount (MIA) of 300, 250, and 350 µg/disk, respectively (Wang et al. 2007). This endophyte also yields the cytotoxic cytochalasin Q (15) (Wei et al. 2015), which is active against P. falciparum K1 with an IC50 value of 17 µg/mL (Chinworrungsee et al. 2001).

Halorosellinic acid (16), from the endophytic Xylaria sp. YC-10 isolated from the stem of Azadirachta indica from China (Wu et al. 2011), showed antimycobacterial activity against M. tuberculosis with MIC of 200 µg/mL and antimalarial activity against P. falciparum K1 with an IC50 value of 13 µg/mL (Chinworrungsee et al. 2001).

Tyrosol (17), isolated from the endophytic Xylaria papulis gathered from Lepidagathis stenophylla C. B. Clarke ex Hayata in Taiwan (Chen et al. 2016), showed antifungal activity against the dimorphic fungi Coccidioides posadasii, in filamentous phase, and Histoplasma capsulatum, in both filamentous and yeast phases. The MIC and minimum fungicidal concentration range values were 250–4000, 30–2000, and 10–1000 µg/mL, respectively. Tyrosol (17) also decreased the ergosterol content and provoked leakage of nucleic acids by affecting the cell membrane permeability (Brilhante et al. 2016).

Piliformic acid (18) is produced by the endophyte Xylaria cubensis BCRC 09F 0035, isolated from the leaves of the Taiwan plant Litsea akoensis Hayata (Fan et al. 2014), and also from the marine fungus Xylaria sp. PSU-F100 (Rukachaisirikul et al. 2009). Piliformic acid (18) showed antimicrobial activity against S. aureus ATCC 25923 and MRSA with a MIC value of 200 µg/mL for both (Rukachaisirikul et al. 2009).

Cytotoxic agents

Xylaria sp. NC1214, from North Carolina, also yields four new oxygenated guaiane-type sesquiterpenes, xylaguaianols A–D (19–22), the new sesquiterpene isocadinanol A (23), a new α-pyrone, 9-hydroxyxylarone (24), the known sesquiterpenes: epi-guaidiol A (25), gliocladic acid (26), bullatantriol (33), hydroheptelidic acid (67), and four known cytochalasins, C (27), D (13), Q (15), and R (28). Cytochalasins C (27), D (13), and Q (15) were cytotoxic against tumour cell lines PC-3 M, NCI-H460, SF-268, MCF-7, and MDA-MB-231. Cytochalasin D (13) presented the highest cytotoxicity against the five cell lines with an IC50 range of 0.22-1.44 µM, and selectivity for line NCI-H460 with an IC50 value of 0.22 µM. Cytotoxicity of cytochalasins C (27) and Q (15) against cell lines PC-3 M, NCI-H460, SF-268, and MDA-MB-231 was moderate, IC50 values range from 0.96 to 1.72 µM for 27 and from 1.31 to 1.53 µM for 15; for line MCF-7, both IC50 values were higher than 5 µM (Wei et al. 2015). Furthermore, Pongcharoen et al. (2007) established that cytochalasin D (13) isolated from the fungus Xylaria sp. BCC 9653, was cytotoxic towards African green monkey kidney fibroblast (Vero) cells with an IC50 value of 0.19 µM. Cytochalasin Q (15) is also cytotoxic against KB and BC-1 cell lines, with IC50 values of 3 and 1 µg/mL (Chinworrungsee et al. 2001).

Gliocladic acid (26), which has already been isolated from three fungal strains Chaetomium globosum SANK 13379, Gliocladium virens SANK 12679, and Trichoderma viride SANK 13479, is an antitumor agent on Sarcoma-37 cell line. Mice treated with a dose of 3 mg/kg/day showed 46% reduction of tumour growth and suppressed the tumour completely at 200 mg/kg (Itoh et al. 1982).

The new cytochalasin H (29) and cytochalasin H2 (30) were isolated from cultures of Xylaria sp. A23, an endophyte of Chinese Annona squamosa. Cytochalasin H2 (30) was cytotoxic against HeLa and 293T cell lines, at a concentration of 1 µg/mL, with inhibition of 32.8 and 25.0%, respectively (Li et al. 2012). Cytochalasin H (29) was cytotoxic towards human leukemia K562 cell line, with an IC50 value of 10.1 µM (Xu et al. 2009), and had anti-angiogenic activity on human umbilical vein endothelial cells (HUVEC), it suppressed HUVEC proliferation at concentrations ≥125 nM. It also showed in vivo anti-angiogenic effects in mice at concentrations ≥250 nM, and at concentrations ≥1000 nM angiogenesis was completely inhibited (Lee et al. 2014).

Cytochalasin B (31) was obtained from X. psidii KT30 (Tarman et al. 2011). It is a microfilament-disrupting agent that modifies many aspects of cell physiology. It showed antitumor activity in vivo against Lewis lung carcinoma, LA4 adenocarcinoma, M109 lung carcinoma, B16F10 melanoma, and P388/S and P388/ADR leukemia. It also reduces metastatic progression in mice. Additionally, 31 was safely administered by multiple routes using murine models (Trendowski et al. 2015).

It is also important to emphasize that cytochalasin inhibited actin polymerization in vitro and induced depolymerization of actin filaments in vitro (Casella et al. 1981).

5-carboxylmellein (4) also showed cytotoxic activity against KB and BC-1 cell lines with and an IC50 value of 3 µg/mL for both cell lines (Chinworrungsee et al. 2001).

Ergosterol peroxide (5), isolated from the endophytic Xylaria sp. SNB-GTC2501, also showed significant cytotoxic effects towards MRC5 cells with an IC50 of 1.9 µM (Sorres et al. 2015). It should be noted that Wang et al. in 2008 reported that compound 5 is cytotoxic against P388, HL-60, A549, and BEL-7402 tumor cell lines with IC50 values of 6.7, 15.3, 86.0, and 61.0 µM, respectively (Wang et al. 2008).

Cerevisterol (32) is a common compound produced by fungi, and is cytotoxic against P388 leukemia cell line with an IC50 of 0.12 µM (Li et al. 2007). This compound has been isolated from Xylaria sp. YC-10, endophyte of A. indica (Wu et al. 2011).

Antioxidant agents

Cerevisterol (32) is also an antioxidant compound with free radical-scavenging activity (SC50) of 5.75 µg/mL (Cateni et al. 2015).

Tyrosol (17) is the major biophenol constituent on olive oil and showed antioxidant activity when added to Caco-2 human cell line (colon adenocarcinoma) with oxidized low density lipoproteins (LDL). A concentration of 0.5 mmol/L of tyrosol (17) hindered the changes that oxidized LDL induce in Caco-2 cells (Giovannini et al. 1999). This compound was also identified from endophytic fungus X. papulis (Chen et al. 2016).

Post-menopausal osteoporosis agents

Bullatantriol (33) was obtained from Xylaria sp. NC1214 (Wei et al. 2015) and also from the plant Homalomena occulta (Hu et al. 2008). It stimulated differentiation of osteoblasts with significant effects of 27.2, 24.6, and 28.7, measured as alkaline phosphatase (ALP) activity in U/10 L, at concentrations of 5.16 × 10−5, 5.16 × 10−6, and 5.16× 10−7 mol/L, respectively (Hu et al. 2008).

Anti-inflammatory agents

The chemical study of the organic extract of X. cubensis BCRC 09F 0035, isolated from the leaves of the Taiwanese plant Litsea akoensis Hayata, led to the isolation of six new metabolites and seven known compounds. The new compounds are: the sesquiterpenoids 10-hydroxythujopsene (34), akotriol (35), and xylaritriol (36), the diterpenoid cubentriol (37), the aliphatic derivative akoenic acid (38), the alkaloid akodionine (39); additionally, the following known compounds were isolated: the isocoumarin akolitserin or xylarellein (9), (–)-(R)-5-(methoxycarbonyl) mellein or 5-carbomethoxymellein (12), (–)-7-(R)-hydroxymellein (40), (R)-5-methylmellein (3), (R)-8-methoxymellein (41), (S)-8-methoxymellein (42), (+)-(S)-piliformic acid (18), methyl 1H-indole-3-carboxylate (43), and 4-(2-hydroxyethyl)phenol (44). Compounds 12, 18 and 38 were tested for anti-inflamatory activity in lipopolysaccharide-activated RAW 264.7 murine macrophages. Only (–)-(R)-7-hydroxymellein (40) inhibited the proinflammatory cytokine interleukin-6 (IL-6) with an IC50 value of 9.4 µM (Fan et al. 2014).

X. papulis produces two new isopimarane-type diterpene glycosides compounds, xylapapusides A (45) and B (46), and five known compounds, elaeicolaside B (47), tyrosol (17), N-acetyltyramine (48), hypoxylonol A (49), and xylaranol B (75). Compounds 45-47 and 48 were tested for anti-inflammatory activity in lipopolysaccharide-activated RAW 264.7 murine macrophages. Nitric oxide (NO) production and cell viability were measured at a concentration of 100 µM. Compounds 45–47 were the most active, showing NO production induced values of 65.7, 88.7 and 78.3%, compound 48 induced 105.2% of NO production. Cell viability was not affected (Chen et al. 2016).

Hypoglycemic agents

The endophyte Xylaria feejensis was isolated from Hintonia latiflora a plant from Mexico, widely used as an antidiabetic herbal drug in Mexico and Europe. The following compounds were isolated from its extract: pestalotin 4′-O-methyl-β-mannopyranoside (50) and 3S,4R-(+)-4-hydroxymellein (51), two new natural product; and five known compounds, 3S,4S-(+)-4-hydroxymellein (52), 3S-(+)-8-methoxymellein (42), (4S,5S,6S)-4-hydroxy-3-methoxy-5-methyl-5,6-epoxycyclohex-2-enone or coriloxine (68), 2-hydroxy-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (69), and 4R,5R-dihydroxy-3-methoxy-5-methylcyclohexen-2-en-1-one (53). The isocumarins 51 and 52 inhibited S. cerevisiae α-glucosidase (αGHY), with IC50 values of 441 and 549 μM, respectively, and their activity was comparable to that of acarbose (IC50 of 545 μM). Compounds 51 and 52 can be considered for type II diabetes mellitus treatment. In addition, molecular docking predicted that they bind to αGHY in a site different from the catalytic domain thus suggesting an allosteric type of inhibition (Rivera-Chávez et al. 2015).

Agricultural potential

Insecticidal agents

The endophyte Xylaria sp. XC-16 from Toona sinensis, a plant that grows in China, produces two new cytochalasans, cytochalasin Z27 (54) and cytochalasin Z28 (93), together with three known metabolites, seco-cytochalasin E (55), cytochalasin Z18 (56), and cytochalasin E (57). Cytochalasin E (57) was the most active compound. It was toxic against brine shrimp with a LC50 of 2.79 μM, which is comparable to the commercial insecticidal toosendanin (LC50 = 4.03 μM). Compounds 54-55 and 93 showed low toxicity toward brine shrimp, ≤10% mortality at 50 μM (Zhang et al. 2014).

Xylaria sp., isolated from Vitis labrusca collected in Canada, produces two new compounds, 13-O-methyl-(5R) diplosporin (58) and agistatine D (59), and the known compounds coriloxine (68), 3-methoxymethyl derivative of agistatine D (60), (5R)-diplosporin (61), 5-carboxylmellein (4) and 5-methoxycarbonylmellein (12). Compounds 59-61 did not show antibacterial or antifungal activity against B. subtilis, Pseudomonas fluorescens and S. cerevisiae (Ibrahim et al. 2014). However, in a previous study, diplosporin (58) was toxic to Spodoptera frugiperda. It suppresses the growth rate of S. frugiperda to 50% when added at 1000 µg/mL to artificial diet (Wicklow et al. 2011).

The chemical study of organic extract from endophytic Xylaria sp. YC-10 isolated from A. indica led to the identification of eleven known metabolites: 5-hydroxymellein (62), 5-methylmellein (3), 5-carboxylmellein (4), hymatoxin C (63), hymatoxin D (64), halorosellinic acid (16), cerebroside C (65), (2S,3S,4R,2′R)-2-(2′-hydroxytetra-cosanoylamino)octadecane-1,3,4-triol (66), cerevisterol (32). All the compounds showed weak insecticidal activity against third instar larvae of Plutella xylostella at concentrations of 5 mg/mL, using the conventional leaf disk method (Wu et al. 2011). Even though their insecticide activity is low, they can be considered as prototypes for preparing semisynthetic derivatives in order to improve their insecticidal potential.

Hydroheptelidic acid (67) isolated from Xylaria sp. NC1214 (Wei et al. 2015), were previously identified in the fungal endophyte of balsam fir Abies balsamea L., Phyllosticta sp. strain 76. This compound was toxic to the spruce budworm Choristoneura fumiferana Clem. (12% of survival) when 16.8 µmol of compound was added to artificial diet (Calhoun et al. 1992).

Phytotoxic agents

The strain SM3e-1b, identified as X. feejensis, produces phytotoxic compounds against seedlings of Trifolium pratense, Medicago sativa, Panicum miliaceum, and Amaranthus hypochondriacus. X. feejensis SM3e-1b was obtained from leaves of Mexican Sapium macrocarpum and the chemical study of its organic extract led to the isolation of three known metabolites: coriloxine (68), 2-hydroxy-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (69), and 2,6-dihydroxy-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione or fumiquinone B (70). In addition, four semisynthetic compounds from coriloxine (68) were prepared: (4R,5S,6R)-6-chloro-4,5-dihydroxy-3-methoxy-5-methylcyclohex-2-enone (68a), 6-hydroxy-5-methyl-3-(methylamino)cyclohexa-2,5-diene-1,4-dione (68b), (4R,5R,6R)-4,5-dihydroxy-3-methoxy-5-methyl-6-(phenylamino)cyclohex-2-enone (68c), and 2-((4-butylphenyl)amino)-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (68d). The seven compounds showed phytotoxic effect on the four weeds and on three physiological processes: germination, root elongation and seedling respiration. The IC50 range was of 0.2 to >1.2 mM for germination, 0.1 to >1.2 mM for root growth, and 0.7 to >1.2 mM for seedling respiration in the four plants. Inhibition is comparable to that of herbicides glyphosate and hexazinone (García-Méndez et al. 2016).

It is known that the fungi which produce VOCs are useful for mycofumigation or biofumigation against weeds and microbial plant pathogens (Stinson et al. 2003; Macías-Rubalcava et al. 2010). In relation to genus Xylaria, only one endophytic isolate is reported as VOCs producer: Xylaria sp. PB3f3, an endophyte from Mexican Haematoxylon brasiletto, it yields 40 volatiles during its growth time, including alkanes, esters, sesquiterpenoids, alcohols, amines, ketones, carboxylic acids, and one ether. The major compounds are thujopsene (71) and 3-methyl-1-butanol (72), at 10 days of culture; an unidentified amine and 2-methyl-1-butanol (73) at day 20; and 2-methyl-1-propanol (74) at day 30. Volatiles are phytotoxic against A. hypochondriacus and Solanum lycopersicum, and the pure compounds 2-methyl-1-propanol and 2- methyl-1-butanol significantly suppress the germination and root growth of A. hypochondriacus and S. lycopersicum in an IC50 value range of 4.6-130 µg/mL (Sánchez-Ortiz et al. 2016).

Cytochalasin H (29), isolated from Xylaria sp. A23 (Li et al. 2012), acts as a plant growth regulator in tobacco. At a concentration of 10−2–10−4 M, it inhibits the floral development of tobacco plants (Wells et al. 1976).

Cytochalasin E (57) isolated from the endophytic Xylaria sp. XC-16, also showed phytotoxic effects on Lactuca sativa and Raphanus sativus L. seedlings in a range of 10–80 μM, which is higher than that of glyphosate (Zhang et al. 2014).

Borgschulte et al. (1991) reported that hymatoxins C (63) and D (64) are phytotoxins because that cause necrosis in leaves and suppress cambium development. These compounds have been isolated from the endophyte Xylaria sp. YC-10 (Wu et al. 2011).

Cerebroside C (65), a glycosphingolipid isolated from Xylaria sp. YC-10 (Wu et al. 2011), induces tolerance at low temperatures on Triticum aestivum. Seed germination rate and root growth increased when cerebroside C (65) was added to media at a concentration of 20 µg/mL. Germination rate was higher (77.8%), germination time shorter (6.19 days), and root growth increased by 13.7% compared to controls (Li et al. 2013).

Xylaranol B (75), isolated from the endophytic fungus X. papulis (Chen et al. 2016), showed phytotoxic activity on radish seeds (Raphanus sativus) at a concentration of 100 mg/mL, inhibiting approximately 60% of seed germination, which is comparable to the inhibition caused by glyphosate (75%) (Amand et al. 2012).

Antifungal agents

The new guaiane sesquiterpenes (1S,2S,4S,5S,7R,10R)-guaiane-2,10,11,12-tetraol (76), (1S,2S,4R,5R,7R,10R)-guaiane-2,4,10,11,12-pentaol (77), (1S,4R,5S,7R,10R)-guaiane-4,5,10,11,12-pentaol (78), (1R,4S,5R,7R,10R)-guaiane-1,5,10,11,12-pentaol (79), and (1R,4R,5R,7R,10R)-11-methoxyguaiane-4,10,12-triol (80) were isolated from Xylaria sp.YM311647 of chinese A. indica. All the compounds were antifungal against Pyricularia oryzae and Hormodendrum compactum, showing MIC values from 32 to 256 µg/mL. Compounds 78–80 inhibited the growth of C. albicans with MIC values of 64 µg/mL for compound 78 and, 32 µg/mL, for compounds 79 and 80. In addition, compound 78 inhibited A. niger and H. compactum, MIC value of 64 µg/mL (Huang et al. 2015). This isolate also yields nine oxygenated guaiane-type sesquiterpenes: (1S,4S,5R,7R,10R,11R)-guaiane-5,10,11,12-tetraol (81), (1S,4S,5S,7R,10R,11S)-guaiane-1,10,11,12-tetraol (82), (1S,4S,5R,7R,10R,11S)-guaiane-5,10,11,12-tetraol (83), (1S,4S,5S,7R,10R,11R)-guaiane-1,10,11,12-tetraol (84), (1R,3S,4R,5S,7R,10R,11S)-guaiane-3,10,11,12-tetraol (85), (1R,3R,4R,5S,7R,10R,11R)-guaiane-3,10,11,12-tetraol (86), (1R,4S,5S,7S,9R,10S,11R)-guaiane-9,10,11,12-tetraol (87), (1R,4S,5S,7R,10R,11S)-guaiane-10,11,12-triol (88), (1R,4S,5S,7R,10R,11R)-guaiane-10,11,12-triol (89); and three isopimarane diterpenes: 14a,16-epoxy-18-norisopimar-7-en-4a-ol (90), 16-O-sulfo-18-norisopimar-7-en-4a,16-diol (91), 9-deoxy-hymatoxin A (92). The sesquiterpenes were active against C. albicans and H. compactum with MIC values ranging from 32 to 256 μg/mL, they also showed moderate or weak antifungal activities against A. niger, P. oryzae, and H. compactum. Furthermore, the diterpenes were more active, compound 92 had a MIC value of 16 μg/mL against C. albicans and P. oryzae, and of 32 μg/mL against A. niger (Wu et al. 2014).

Cytochalasin Z28 (93) isolated from the endophyte Xylaria sp. XC-16, displayed antifungal activity against the plant pathogen Gibberella saubinetti (MIC of 12.5 μM), it was more active than the fungicide hymexazol with a MIC value of 25 μM (Zhang et al. 2014).

The nonenolide named xyolide (94), (4S,7S,8S,9R)-4-O-succinyl-7,8-dihydroxy-9-heptyl-nonen-9-olide, was isolated from the Amazonian endophytic fungus X. feejeensis from Croton lechleri. Compound 94 is active against the plant pathogenic oomycete Pythium ultimum with a MIC value of 425 µM (Baraban et al. 2013).

Interestingly, various isolates of Xylaria produce griseofulvin (95); Xylaria sp. strain F0010 isolated from Abies holophylla (Park et al. 2005), Xylaria sp. PSU-G12 from G. hombroniana (Rukachaisirikul et al. 2013), X. cubensis from Asimina triloba (Sica et al. 2016), 13 strains of Xylaria sp. Isolated from Pinus strobus, and six strains from Vaccinium angustifolium (Richardson et al. 2014). Some of these strains also produce dechlorogriseofulvin (96) (Park et al. 2005; Rukachaisirikul et al. 2013; Richardson et al. 2014). Griseofulvin (95) inhibits the growth of fungal plant pathogens, but not of oomycetes (Richardson et al. 2014). It inhibits Alternaria mali, Botrytis cinerea, Colletotrichum gloeosporioides, Corticium sasaki, Fusarium oxysporum and Magnaporthe grisea in in vitro experiments, with IC50 values of 18.0, 5.0, 1.7, 11.0, 30.0, and 1.7 µg/mL, respectively. Dechlorogriseofulvin (96) showed weak antifungal activity, with an IC50 value >200 µg/mL for each fungi. It has also been demonstrated that griseofulvin (95) inhibits M. grisea, C. sasaki, B. cinerea, Puccinia recondite, and Blumeria graminis f. sp. hordei in in vivo experiments, with a percentage of fungal control of 95, 100, 60, 90 and 90, respectively, at 150 µg/mL. Furthermore, dechlorogriseofulvin (96) at 150 µg/mL has 70, 25 and 93% of fungal control for C. sasaki, B. cinerea and B. graminis f. sp. hordei in vivo (Park et al. 2005). Nowadays, griseofulvin (95) is used for the treatment of skin diseases caused by fungi such as Trichophyton species (Richardson et al. 2014). These strains may be useful to obtain griseofulvin by biotechnological processes.

Table 1 shows the structures of the secondary metabolites recently isolated from endophytic Xylaria species, and the source and biological activity of each compound. Furthermore, it includes the isolated secondary metabolites that did not show any significant activity in preliminary studies but are nonetheless candidates to further study their biological activity. Finally, four bioactive semisynthetic derivatives are shown.

Table 1 Recently reported bioactive secondary metabolites from endophytic Xylaria species
Full size table

Conclusion

At present, the endophytic fungi research including Xylaria species is basically focused in isolation and identification, and on exploring the biological activity of secondary metabolites produced. However, it is also necessary to deepen the biological, chemical and biotechnological studies of these microorganisms to optimize their use as a potential source of new drugs and agrochemicals, or for development of biocontrol agents. Furthermore, it is well known that production of secondary metabolites is a process highly influenced by several physicochemical factors particularly temperature, pH and oxygenation, and the presence or absence of certain nutrients. Therefore, it is of paramount importance to optimize the culture conditions in order to improve the development of new pharmacological compounds and agrochemical products.

To promote the finding of endophytic Xylaria species, which would potentially produce new bioactive secondary metabolites, there are two main strategies: first, the selection of endophytes that possess an antagonic effect on other microorganisms, including endophytic fungi, human pathogenic fungi, or phytopathogenic fungi with agricultural importance; and second, a dereplication strategy.

The endophytic Xylaria species have been found associated to both vascular and nonvascular plants and, as has been shown in this review, the structural diversity of the bioactive secondary metabolites from endophytic Xylaria species opens the opportunity to finding new compounds, and even new chemical skeletons, that can be used by themselves or as structural prototypes to develop therapeutic agents or as biopesticides. Nevertheless, the bioactive secondary metabolites produced by endophytic fungi, especially the Xylaria species are just beginning to be discovered.

Metabolites such as cytochalasins, guaiane sesquiterpenes, mellein derivatives and coriloxine, are common in Xylaria species and have important biological activity. Particularly, cytochalasins are the most important bioactive components in the genus Xylaria. These compounds, in addition to being cytotoxic and possessing a high chemical diversity, are a fundamental tool to understanding the importance of actin in various biological processes.